The contribution of I-Abm12 to the production of autoantibodies to dsDNA

Abstract

The development of IgG autoantibodies to dsDNA in NZBxNZW F1 (NZB/W) and NZBxSWR F1 (SNF1) mice have been linked to specific alleles of MHC class II genes contributed by the NZW and SWR parents respectively. Recently, our laboratory has shown that the introduction of the bm12 mutation into NZB mice (NZB.H-2bm12) results in mice which are phenotypically similar to NZB/W F1 mice and, in particular, develop IgG anti-dsDNA antibodies. A variety of immune abnormalities have been described in autoimmune NZB (H-2d) mice. It is, however, unclear at present, whether all these abnormalities are due to the influence or effect of a single set of linked genes or due to multiple genes. It was reasoned that NZB.H-2bm12 mice provide a unique opportunity to examine this issue. Specifically, we bred a series of five different F1 colonies of mice: (a) NZB.H-2bm12/b F1; (b) NZB.H-2bm12/d F1; (c) NZB-H-2b/d F1; (d) NZB-H-2bm12 x B6.C-2bm12 F1 (NZB/B6.H-2bm12 F1); and (e) NZB x B6.C-H-2bm12 F1 (NZB/B6.H-2d/bm12 F1) mice. All groups of mice were serially followed for the appearance of IgM and IgG anti-ssDNA and anti-dsDNA antibodies, splenic CFU-B, spontaneous secretion of IgM, FMF analysis, proteinuria and survival. We report herein that H-2bm12 genes have a dominant influence on the appearance of IgG anti-dsDNA antibodies. In contrast, antibodies to ssDNA, IgM secreting cells, CFU-B and Ly-1 B cells are linked to genes from the NZB background. Finally, we particularly note an absence of IgG antibodies to dsDNA in NZB-H-2b/d F1 mice.